CD4+T细胞通过CCL5/STAT3-SIRT1信号通路调控自噬促进去势抵抗前列腺癌化疗耐药的机制研究

多西他赛化疗是转移性去势抵抗前列腺癌（CRPC）的一线治疗方案，目前面临的最大瓶颈仍然是治疗过程中肿瘤耐药难题。探究CRPC化疗耐药的免疫微环境调控机制，并增加肿瘤化疗敏感性是本项目的关键。我们前期工作发现CRPC发生化疗耐药的前列腺癌标本中，肿瘤区域较非肿瘤区域CD4+T淋巴细胞明显增多，并且在共培养体系中通过释放CCL5因子激活CRPC细胞自噬信号诱导化疗抵抗。我们推测，在肿瘤微环境中CD4+T细胞分泌的CCL5能激活前列腺癌pSTAT3，通过识别SIRT1启动子区域GAS样序列增强其转录，并可能经过翻译后修饰促进SIRT1蛋白表达，打破STAT3-SIRT1“对话”，以AR非依赖途径诱导自噬发生，从而促进多西他赛抵抗。本课题深入研究CCL5/STAT3-SIRT1信号通路在化疗耐药中的分子机制，调控关键环节逆转CD4+T细胞诱导的化疗抵抗，为临床晚期前列腺癌提供新的治疗方案。

Docetaxel-mediated chemotherapy is the first-line treatment for metastatic castration-resistant prostate cancer (CRPC) patients, but its therapeutic benefit is limited by the development of drug resistance, which ultimately leads to tumor progression and patients death. The aims of this project are to explore the regulatory mechanism of CRPC chemoresistance in tumor immune microenvironment and to increase the chemotherapy sensitivity. Our previous research found that there were more infiltrated CD4+T cells in human prostate cancer(PCa) lesions than in the adjacent noncancerous tissues after Docetaxel treatment. Moreover, CD4+T could secrete large amounts of CCL5 factors to induce autophagy and chemotherapy resistance in the coculture system. We hypothesize that CCL5 secreted by CD4+T cells in the tumor microenvironment can activate pSTAT3, which enhances its transcriptional activity by identifying and binding the GAS-like sequence in the SIRT1 promoter region, and possibly promote SIRT1 protein expression through post-translational modifications. Consequently, CCL5 break the STAT3-SIRT1 "cross-talk", and induce autophagy by AR independent pathway, and thus promoting tumors’ resistance to Docetaxel. We will focus on research on the molecular mechanism of CCL5/STAT3-SIRT1 signaling pathway in CRPC chemoresistance. With regulation of the key factors in the pathway, PCa chemoresistance can be reversed to be induced by CD4+T cells. Our study can provide a new theoretical basis for CRPC chemoresistance and treatment.